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Hugh McGuigan.

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to the element and not to the oxygen or hydrogen compounds.
As soon as it is oxidized, it loses its specific action. The chief
toxic action is to cause fatty degeneration in various organs.
In therapeutic doses, it is used to stimulate bone formation and
growth.

This substance resembles arsenic in many of its reactions.

For details, see Hawk's Physiological Chemistry, 6 Edition, p. 325,



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362



CHEMICAL PHARMACOLOGY



PHs, or phosphine, corresponds to AsHa, or arsine. PH3 has
basic characters like NH3 and unites i/^th acids to form salts
of the general formula PH4X (phosphonium) . These salts are very
weak and are decomposed by water into PHs and HX. Arsine,
AsHs, and stibine, SbHj, do not possess this basic property.
The H atoms in phosphine can be replaced by alkyl groups to
form



<l



or






or



P^R

\r



or



mono

alkyl

phosphine



P^R

^R
\0H
quaternary
phosphoniun
base



dialkyl tertiary

phosphine alkyl

phosphine

Only the tertiary phosphine and the quaternary phosphonium
compounds are formed by the action of alkyl haUdes RI on PHj.
The mono and di alkyl phosphines are obtained by heating phos-
phonium iodide, PHsI, with an alkyl iodide and zinc oxide. These
quaternary phosphonium bases, like those of arsenic, antimony,
etc., exert a strong curare-like action in animals. They are
strongly basic, and when heated, decompose into a hydrocarbon
Cn H2n + 2 and oxygen compound;

(CjHb)* P.OH .= CsHe + (CjHs), PO
An ammonium base under the same conditions would decom-
pose into an alcohol and trialkyl base:
/CjHb



//C2H5
N^C2H5
VC2H5
\0H



= NR3 + CjHbOH



Oxidizing agents oxidize phosphorus to phosphoric acid.

In cases of poisoning with phosphorus, the metal will distil
from an acid solution and can be detected by its phosphorescence
in a dark room. This phosphorescence is due to the process of
oxidation of the metal. Oxidizing agents, like potassium perman-
ganate and hydrogen peroxide in dilute solutions are used as
antidotes in phosphorus poisoning.



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PHOSPHORUS 363

Ag forms a compound with P, AgaP. This test is used in
cases of suspected poisoning with P. A piece of filter paper
moistened with AgNOa, suspended over a solution containing
P turns black if phosphorus is present, due to the formation
jof silvier phosphide AgaP. Other substances like H2S in the
solution will also cause a blackening of the AgNOa paper, and
the test for P is valuable only in proving its absence. Copper
also forms compounds with P. The formula of the copper
phosphide is not definite, probably CuaP or CU2P6. In cases of
acute poisoning with phosphorus, the administration of dilute
copper sulphate 0.5 gram in 100 cc. may be of value in preventing
the absorption of P. which is still in the gastro-intestinal tract.
In addition, the copper solution will also act as an emetic.

The name phosphine may lead to confusion at times, for an
acridine dye, Philadelphia Yellow, is also known by the same
name. Acridine, C13H9N, is prepared from ortho-amino-diphe-
nyl-methane;

^CH2.C.H5 yN ^

C6H4V = C6H4V I yC6H4

^NH2 ^CH^

o. amino diphenyl acridine

methane

Phosphine, or Philadelphia Yellow, is a beautiful yellow dye
which forms red colored salts, and is a mixture of the hydro-
chlorides of asymetrical diamido-m-tolyl acridine. It is obtained
as a by product in the manufacture of rosaniline. Its formula is;



NH2.C6Hf




Phosphine

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364 CHEMICAL PHARMACOLOGY

It is a protoplasm poison, especially for protozoa, but has been
used without success in malaria.

The Fate of Phosphorus in the Body

The fate in the- body is obscure. It is highly probable that
it is oxidized to some extent in the body. It is hard to tell this
from direct chemical examination because the phosphates vary
normally, more than a toxic dose of phosphorus could change the
phosphate content of the urine. Some may be excreted by the
lungs; but the statement that the breath may become phosphores-
pent is not given much weight : Unknown organic combinations of
phosphorus have been found in the urine.

AfeSENIC COMPOUNDS

Metallic arsenic is non-toxic, while its compounds are all
toxic. White arsenic, AS2O3, which is an anhydride of arse
nious acid, AS2O3 + 3H2O = 2H8ASO3, is the most important
compound. Arsenious acid, however, cannot be isolated
since on evaporation of its solution arsenic trioxide is again
obtained. This is also known as white arsenic. A 1 per
cent, solution of this in 2 per cent, potassium bicarbonate
solution is known as Fowler's solution, and is a favorite prepara-
tion in medicine. Asia, arsenious iodide, is also used in medicine
in the form of liquor arseni et hydrargyri iodidi. This is a
1 per cent, solution each of Asia and red mercuric iodide Hgl2
in water. Sodium arsenate, Na2H.AsO4.7H2O is used to some
extent.

Atoxyl, sodium arsinalate, or sodium p amino-phenyl arsenate
is a compound formed when anilin and arsenic acid are heated
together

/OH
CcHbNHj + As(0H)3 = C6H5NH2 - O - As=0

\0H
p. amino-phenyl arsenate
/OH
NH2C6H4 - As-0 = + H2O
\0H

p. amino-phenyl arsenic acid

Digitized by CjOOQ IC



ARSENIC 365

The sodium salt of this is atoxyl. The Na replaces an hydroxyl H.

/OH
Acetyl aioxyl CHa.CO.NH.CeH4. — As =0 is also employed.

\0H

Arsacetin is the sodium salt of this, or

/OH
CHsCO-NH-CH* - As'^O

\ONa

,0H
/oH
//.OH
Arsenic acid has the formula H3ASO4 or As^

^O

When two of the OH. groups are replaced by methyl groups, we
have cacodylic acid: —

/CH3
As^CHa
^OH ■
^0
Cacodylic acid is formed when potassium acetate is distilled with
arsenious acid: —

AsjO, + 4CH3COOK -> (CHa)^ = As - O - As = (CH,)!

+ 2KjC03 + 2CO2
cacodyl oxide
Cacodylicoxide when treated with HCl yields cacodyl chloride:
(CH3)2 = As - O - As = (CH3)2 + HCl = 2(CH3)2 As - CI.
On oxidation this yields cacodylic acid :

/CH3 yCHs

As— CH3 + 2H2O + 20 -^ 2 As— CH3
\C1 II^OH


/CI
As— CH3
\CH3
Sodium cacodylate is the most important salt of cacodylic acid.

/CH3

= As^CH,

\ONa



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366 CHEMICAL PHABMACOLOQT

If the three hydroxyl hydrogens of arsenic acid are replaced by
Na, sodium arsenate is the product. This, acted upon by
methyl iodide in alkaline solution, yields sodiiun methyl arsenate
or arrenhal.

/ONa /CHa

O = As— ONa + CH,1 = O = As— ONa

\ONa \ONa

Sodium arsenate arrenhal

Arsphenamine or salvarsan "606" dioxy diamino arseno benzol
The niunber "606" refers to the laboratory research number.
This substance is a derivative of arseno benzene,

C»H6- As = As - CHs,

which is analogous to azo benzene,

C,Hs - N = N- CeHs.

The fallowing reactions illustrate its preparation:

(I) When phenol and arsenic acid are heated together a conden-
sation takes place in the para position:

,0H



H0<



HHO



- As-0 =



HO

OH



H0< >As==0 + H80

"^OH
p. phenol arsenic acid

When this is treated with nitric acid, a nitro derivative is formed:

,0H

0H< >As==0+HONOj =

^OH

NO,

.OH

0H<; > A8=0 +H2O

^OH



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ABSPHENAMINE 367

On complete reduction, this yields a condensation product:

NO2

/OH
(2) 0H<^ > As = O + 2 OH -^

\0H

As As



NH2



NH2



OH salvarsan OH



Arsphenamine or salvarsan is a light yellow crystalline powder
and yields a solution in water with an acid reaction. When given
irjtravenously, the solution should be well diluted and slightly
alkaline.

Neo-arsphenamine or neo-salvarsan, (914) is a soluble prepa-
ration of salvarsan. It is sodium di-amino dihydroxy arseno-
benzene methanal sulphoxylate;



As=



=As



NII2



NH(CH20)0SNa



OH



OH



It is prepared by precipitating a salt of arsphenamine with
sodium methanal sulphoxylate and dissolving the precipitate
in alkalies. It is an orange yellow powder of peculiar odor and
is unstable in the air.

Fate of Arsenic in the Body

Arsenic is absorbed rapidly and excretion by the urine begins
in about seven hours and lasts several days, though it may con-



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368 CHEMICAL PHARMACOLOGY

tinue for three months. It is excreted mainly through the kid-
neys. Since it irritates the kidneys the amount of urine in toxic
cases is greatly diminished.

Regarding the retention of arsenic by the various organs, the
liver retains the most, but the kidneys, spleen and muscles all
may contain arsenic. Only traces are found in the br^tin. It has
been detected in the cancellous bones of the skull and vertebra*
after it has disappeared from all the other organs. The poison
is probably combined in the organs as arseno-nucleins. Since
the nucleins are the most active seats of life it probably kills by
an action here.

Binz and Schultz thought that the action of arsenic was due
to an alternate reduction and oxidation of it in the tissues.
Arsenious acid being oxidized to arsenic acid and the reverse
reaction occurring also. In this way oxygen is alternately
withdrawn from and supplied to the protoplasm. If such a
process takes place it must be very gradual otherwise we cannot
explain why arsenious acid is so much more powerful than arsenic
acid.

Gautier thought arsenic to be a normal constituent of the
thyroid gland, but there seems to be no basis for this, and what
Gautier found must have been taken as medicine or otherwise.

For a complete report on the Chemistry of the Organic Com-
pounds of Arsenic and Antimony — see Organic Compounds of
Arsenic and Antimony by Gilbert T. Morgan, Longmans Green
and Co. 1918.

XXXUI. HEAVY METALS

We include under the term heavy metals, antimony, mercury,
iron, lead, copper, zinc, silver, bismuth, aluminum, gold, plat-
inum, manganese, cadmium, nickel, cobalt, tin, thallium, van-
adium, timgsten, uranium, etc. Of these, only the first twelve
are of importance in medicine, the others being of toxicologic
interest only. Phosphorus and arsenic are important, but; they
are not usually classified with heavy metals.

The metals themselves are inactive, and it is only in the form
of soluble salts that they exert any action. It must be remem-
bered, however, that the solubility in albumen may be different
from that in water, although usually only those salts that are
soluble in water are active.



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HEAVY METALS 369

Heavy metals have two actions: (1) local, and (2) general,
or the action after absorption.

The salts of the heavy metals form combinations with proteins,
and local action is due to this combination. According to the
reactivity, strength, and extent of the combination, the salts of
the heavy metals may be astringent, irritant, styptic, caustic or
* corrosive. Since the same salt in different concentrations may
exhibit all these actions, it is impossible to classify metals under
these heads. From a practical standpoint, however, they may
be classified as follows:

1. Styptics — ferric chloride, dried alum.

2. Astringents — alum, lead acetatp, basic lead acetate, zinc
oxide, bismuth subnitrate, ammoniated mercury.

3. Astringent and corrosive — iron salts, zinc sulphate, zinc
acetate, copper acetate, silver nitrate, lead nitrate, lead iodide.

4. Corrosive — mercury salts, zinc chloride, tin chloride, anti-
mony chloride, copper sulphate.

As a rule, the greater the ionization, the greater the action.

The salt formed by the union of a metal with protein is a pro-
teinate, e.gf., argenti proteinas or protargol. It is not of constant
composition, but varies with the kind of protein and the amounts
of the protein and metal used. Thus the salts are not true chem-
ical compounds. The precipitate when fornied may redissolve,
or go again into solution if too* much of the reagent or of the
protein solution is added. This is especially true in the case of
lead salts, and is readily understood in the light of the phenome-
non of precipitation.

Explanation of Precipitation

Proteins are emuJsoid colloids. Colloids remain in solution
because they are electrically charged, either negatively or posi-
tively. Proteins belong to the class of colloids, which are usu-
ally negative, and remain in solution as long as they retain this
charge. Because the charge is the same throughout, and as Uke
charges repel each other, the protein remains in solution but
when the charge is neutralized, precipitation occurs. According
to the cause, precipitation may be due to:

1. Spontaneous precipitation.

2. Gelatinization.

24



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370 CHEMICAL PHARMACOLOGY

3. Coagulation by enzymes and heat.

4. The addition of electrolytes.

5. Other colloids of opposite sign.

Examples of these changes in drug chemistry are:

1. The spontaneous decomposition of a solution of siUcic acid
or water glass.

2. The precipitation of gelatin or agar due to loss of water by
evaporation. Their solution may be considered as hydrophyUc
compounds. Evaporation necessitates an internal rearrange-
ment and a loss or neutralization of the charge. These charges
are reversible, an addition of water again causing the formation
of a colloidal solution.

3. Heat coagulation, and the changes caused by enzymes are
well known in the coagulation of white of egg, and the souring
of milk. These coagulations are irreversible.

4. The precipitates formed by electrolytes are divided into
two groups (reversible and irreversible), depending on the na-
ture of the precipitate or coagulate.

Salts of Ba.Sr. and the heavy metals form precipitates which
are irreversible.

The difference between reversible and irreversible precipitates
is due to a fundamental change and molecular rearrangement in
the case of the irreversible; while in the reversible there is merely
a neutralization of the electrical charge. Accordingly, proteins
may be precipitated in three forms:

1. Unaltered, i.e., by salting out or neutralization of the
charge — reversible.

2. As albuminates, by coagulation 1 . ., ,

3. Insoluble salts of metals /

Both ions of a salt are important in precipitation. Which of
the two is more important depends on the nature of the colloid
to be precipitated. For example: colloidal iron is a positive
colloid, and is much used to remove proteins from the blood.
The positive charge on the iron salt is neutralized by the negative
charge on the protein and both are precipitated. Colloidal iron
is also precipitated by a solution of MgSOi, or Na2S04 or almost
any salt. In this case it is the negative ion or anion which acts
to neutralize the positive charge of the iron.

In the precipitation of proteins, however, the same explanation



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COLLOIDS 371

holds; but since the proteins are negatively charged it is the posi-
tively charged ion or cathion that is more important as a protein
precipitant. Since the precipitation is due to a neutralization, it
follows that if the colloid is negative the precipitating ion is always
the cathion, if positive, the anion.

Bivalent ions are more active in causing precipitation than
monovalent, and polyvalent more powerful than bivalent. The
valence of the ion of the same sign as the colloid has no influence
on the action.

Aside from the neutralizq,tion, there are, of course, especially
with the heavy metals, proteinates formed that can not be
explained on this simple basis. These salts, while not so definite
as the heavy metal combinations with sulphates, carbonates, etc.
are of the same nature.

The action of heavy metals when taken internally is due to the
chemical local action of the metal on the stomach and intestine.
The nature of the acid in the salt is of importance, as is also the
nature of the precipitate, slimy or granular.

Nitrates are more irritant than acetates because the nitric acid
liberated in the reaction is a more powerful irritant than acetic
acid.

When the precipitate is granular, the acid Uberated penetrates
to the tissue below more readily than when the precipitate is
slimy in nature. Corrosive sublimate, for these reasons, pene-
tiates deeper and is more corrosive than lead acetate.

Local reactions of the heavy metals when taken internally are;
loss of appetite, pain and discomfort, nausea, vomiting, purging,
congestion, hemorrhages. These are all the result of the irritant
and corrosive action of the metal. Ulcers may result after a
time due to bacterial action on the dead tissue.

The action after absorption is also the result of a combination
of the metal with the protein.

There is little difference in the action of the metals after ab-
sorption. Iron is just as toxic as arsenic when it is introduced
into the blood, but it is not absorbed rapidly from the stomach;
consequently it is not ordinarily toxic.

The toxic action of the heavy metals on the central nervous
system is manifested by delirium, hallucinations, mania, stupor,^
and coma. Convulsions indicate that the motor areas, basal



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372 CHEMICAL PHARMACOLOGY

ganglia and spinal cord are affected. Peripheral neuritis occurs
especially with lead and antimony, not differing from the neuri-
tis caused by alcohol, arsenic or toxins.

The astringent action of the heavy metals is due to several
factors:

1. The metal and protein unite to form an albuminate, and the
resultant liberated acid has an astringent effect.

2. The metal may be absorbed locally and exert a constricting
action on the local vessels.

3. Insoluble salts Uke cerium and» bismuth cover and protect
the surface mechanically.

Absorption of heavy metals is slow, with the exception of salts
of mercury. Mercury is the only volatile metal and volatility
aids absorption. Whether the volatile character of the free
metal conveys any properties on the ion in the salt is not known.

The matter of excretion of heavy metals may be described as
follows; the body stores up the metals in the liver, spleen and
other organs, slowly eliminating it from them. This is done by
the kidneys and intestine, thus showing the reason that nephritis
is a prominent symptom. Heavy metals are also excreted into
the gut, and have a specific action on the gastro-intestinal tract.
This effect is more marked with arsenic, phosphorus and anti-
mony than with the heavy metals. By whatever course they
enter the body, there is always an inflammation of the gastro-in-
testinal tract throughout its extent, as much of the metal leaves
the body by this route.

COLLOIDAL METALS

The colloidal metals especially used in medicine are gold, cop-
per, platinum and silver. These are simply finely divided metals
having an electrical charge, which is positive. They are suspen-
soid colloids.

The methods for preparing colloidal metals are:

1. The disintegration of heavy metals by means of an electric
current strong enough to cause sparks under water. The metal
is used as electrodes.

2. Reduction of dilute solutions of the salts of the metals by
various reducing agents. They are prepared in water free from
electrolytes as they can not be kept for any time in the presence of
salts.



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INORGANIC ACIDS 373

The method of preparation by an electric current, and the effect
of ' electrolytes in causing precipitation, together sustain the
opinion that colloids bear electric charges. This properly differ-
entiates true suspensions from suspensoid colloids. True suspen-
sions will settle out on standing at rest, while suspensoid colloids
are Uttle influenced by gravity and remain suspended.

The basis for the use of colloidal metals in medicine is that
traces of copper and other heavy metals in water in a vessel of
one of these metals, contain none of the metal detectable by
chemical means, yet they prevent the growth of, and sometimes
kill, unicellular organisms. When the metallic surface is in-
creased as in the colloidal solutions, a greater chance is given for
this action, and the colloidal solutions can be injected into tumors
or appUed to miicous surfaces. The value of colloidal metal
solutions is still problematical, for while solutions such as argenti
proteinas imquestionably is efficient in some infections of the
eye, it is probably less efficient than a.l per cent, solution of
silver nitrate.

XXXIV. INORGANIC ACIDS

The inorganic acids of importance in pharmacology are boric,
hydrochloric, sulphuric, nitric and phosphoric. Chromic and
hydroflouric acid are of small importance.

The acids when used as such owe their action to the hydrogen
ion, and are protoplasm poisons. Protoplasm, which is essen-
tially alkaline in reaction, cannot contain life if this alkaUnity is
neutralized by acids. If strong acids come in contact with pro-
toplasm, they may disintegrate it, hence they are corrosive poi-
sons. For this reason, strong acids, when applied to the skin,
destroy the epidermis. Acids, because of this corrosive action,
are sometimes used to destroy warts. The corrosive action is
more marked when the acids are applied to mucous membranes;
even a small quantity of a strong acid in the eye may destroy the
sight. The mucus membrane of the mouth, esophagus and stom-
ach may be destroyed if such acids are swallowed. In dilute
solutions, they are absorbed rapidly, and are neutralized, and
exist in the blood in the form of salts.

The process of neutralization differs in different animals.
Herbivora, because of their food, have a greater reserve of fixed



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374 CHEMICAL PHARMACOLOGY

alkalies, mainly sodium and potassimn, which are first used to
neutralize anj^ acid that may be taken. When these alkalies are
used below a certain level, proteins are broken down and ammonia
is fonned to neutraUze the acids. Carnivorous animals, on
the other hand, are accustomed to the development of acids
from their protein food, and as their food contains a limited quan-
tity of fixed alkali, the normal process of neutralization is the
formation of ammonia. Hence carnivorous animals, because
they can more readily form ammonia are in a better position to
protect themselves from the neutralizing influence of acids.
Herbivorous animals consume large quantities of organic salts
of the alkalies in their food, and have a greater immediate reserve
of these salts than carnivorous animals, but the mechanism to
form ammonia quickly is lacking, which is always at work in the
carnivora, and, in case of poisoning, requires only a little speeding
up. Herbivora, then, are more easily poisoned with acids than
carnivora. The absorption of dilute acids in dogs does not mater-
ially change the available alkali of the blood, while in rabbits,
the same amount of dilute acid causes a reduction of from twenty
five volumes to two volumes per cent, in the carbonic acid in the
blood. When this occurs, respiration becomes deep, labored
and rapid, afterwards, weak and shallow, and finally ceases.
The heart continues to beat after respiration has ceased.

The acids are excreted by the kidney in the form of salts. If
any considerable quantity has been taken, the body conserves its
alkali reserve and the salts are excreted as acid salts.

To counteract the effect of acids, alkalies are used: Since most
alkalies themselves are corrosive, one 'must exercise care in their
use. The most available is sodium bicarbonate or baking soda.
This may be used without much danger. Lime water can also
be used, but its neutralizing power is little since calcium oxide
is soluble only in about 800 parts of water. If sodium carbonate,
or sodium hydroxide be used, very dilute solutions can be used
without injury, but if stronger solutions are used they exert a
caustic action perhaps more harmful than the acids.

XXXV. SALT ACTION

By salt action in pharmacology, we understand those actions
which are Hot specific but which may be elicited by any salt,



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SALT ACTION 375

and are due fundamentally to processes of osmosis, diffusion, and
dialysis. The effects of sodium chloride on red blood corpuscles
are an example of salt action. If the salt is iso-tonic, no action
takes place, while if it is hyper tonic, crenation occurs. If the
salt is hypotonic, the cell will absorb water and a swelling or
edematous condition results. If the salt is applied to the nerve
in hypertonic solutions, it will cause a twitching of the muscle
through its action on withdrawing water from the nerve.

Ion action differs from salt action in that the action is specific.

+
Thus, KCN is a pronounced poison because it ionizes into K and

CN. The CN is a violent poison. The same amount of CN



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